Overexpression or amplification of the HER-2 oncogene has been associated with poor survival in node positive breast cancers. We, in CALGB, have discovered that despite this worse outcome, those with perturbations of HER-2 significantly benefit from dose intensive adjuvant chemotherapy resulting in a doubling of the 5 year actuarial survival rates. Our analysis suggests that the important agent in this dose interaction is Adriamycin. Equally important is that patients with no abnormalities of HER-2 do not appear to show the same benefit with high dose treatment. Thus the HER-2 status may define the specific agents and doses that are appropriate for this patient subset. We propose to verify and extend these initial findings by assessing the HER-2/dose interactions in a larger data set. We will study the mechanism of this interaction by determining the whether the expression of the neu differentiation factor (NDF), p53, and the expression and amplification of Topoisomerase II and PRAD-1 will contribute to this dose effect. We will also assess the impact of S phase fraction and the levels of circulating HER-2/c-erbB2 extracellular domain on this interaction. To further enhance this approach, we will obtain data sets from the International Breast Cancer Study Group node positive adjuvant trial, and other CALGB adjuvant trials where the HER-2 status is known, to determine whether specific chemotherapeutic agents, such as Adriamycin, are important in this oncogene/dose interaction.